Toll-like receptor 4 mediates ozone-induced murine lung hyperpermeability via
inducible nitric oxide synthase.
Kleeberger, Steven R., Sekhar P. M. Reddy, Liu-Yi Zhang, Hye-Youn Cho, and Anne E.
Jedlicka.
Department of Environmental Health Sciences, The Johns Hopkins University School
of Public Health, Baltimore, Maryland 21205
APStracts 7:0263L, 2000.
We tested the hypotheses that 1) inducible nitric oxide synthase (iNOS) mediates ozone
(O3)-induced lung hyperpermeability and 2) mRNA levels of the gene for iNOS (Nos2)
are modulated by Toll-like receptor 4 (Tlr4) during O3 exposure. Pretreatment of O3-
susceptible C57BL/6J mice with a specific inhibitor of total NOS (NG-monomethyl-l-
arginine) significantly decreased the mean (±SE) lavageable protein concentration (a
marker of lung permeability) induced by O3 (0.3 parts/million for 72 h) compared with
vehicle control mice. Furthermore, lavageable protein in C57BL/B6 mice with targeted
disruption of Nos2 [Nos2(«minus»/«minus»)] was 50% less than the protein in wild-type
[Nos2(+/+)] mice after O3. To determine whether Tlr4 modulates Nos2 mRNA levels,
we studied C3H/HeJ (HeJ) and C3H/HeOuJ mice that differ only at a missense mutation
in Tlr4 that confers resistance to O3-induced lung hyperpermeability in the HeJ strain.
Nos2 and Tlr4 mRNA levels were significantly reduced and correlated in resistant HeJ
mice after O3 relative to those in susceptible C3H/HeOuJ mice. Together, the results are
consistent with an important role for iNOS in O3-induced lung hyperpermeability and
suggest that Nos2 mRNA levels are mediated through Tlr4.
Received 26 May 2000; accepted in final form 28 September 2000
APS Manuscript Number L173-0.
Article publication pending Am J Physiol Lung Cell Mol Physiol
ISSN 1080-4757 Copyright 2000 The American Physiological Society.
Published in APStracts on 30 November 2000